Solvent/Detergent (SD) treatment of plasma and plasma derivatives to inactivate viruses is well known in the art of eliminating pathogens and depyrogenating plasma derived pharmaceuticals. SD treatment of plasma to inactivated lipid enveloped viruses is also well known. Various SD treatments are described, for example, in U.S. Pat. Nos. 4,315,919 titled DEPYROGENATION PROCESS, issued Feb. 16, 1982 to Shanbrom (Shanbrom '919); 4,412,985, titled DEPYROGENATION PROCESS, issued Nov. 1, 1983 to Shanbrom (Shanbrom '4,481,189, titled PROCESS FOR PREPARING STERILIZED PLASMA AND PLASMA DERIVATIVES, issued Nov. 6, 1984 to Prince (Prince '189); 4,591,505, titled PROCESS FOR INACTIVATING HEPATITIS B VIRUS, issued May 27, 1986 to Prince (Prince '505); 4,764,369, titled UNDENATURED VIRUS-FREE BIOLOGICALLY ACTIVE PROTEIN DERIVATIVES, issued Aug. 16, 1988 to Neurath, et al. (Neurath '369); 4,909,940, titled EXTRACTION OF PROCESS CHEMICALS FROM LABILE BIOLOGICAL MIXTURES WITH ORGANIC ALCOHOLS OR WITH HALOGENATED HYDROCARBONS, issued Mar. 20, 1990 to Horowitz, et al. (Horowitz '940); 5,094,960, titled REMOVAL OF PROCESS CHEMICAL FROM LABILE BIOLOGICAL MIXTURES BY HYDROPHOBIC INTERACTION CHROMATOGRAPHY, issued Mar. 10, 1992 to Bonomo (Bonomo '960); and 5,186,945 titled BLOOD PLASMA ANTIVIRAL PROCESS AND COMPOSITION, issued Feb. 16, 1993 to Shanbrom (Shanbrom '945).
Separation of SD chemicals from the plasma intermediates after SD treatment is described in U.S. Pat. Nos. 5,120,649, titled PHOTODYNAMIC INACTIVATION OF VIRUSES IN BLOOD CELL-CONTAINING COMPOSITIONS, issued Jun. 9, 1992, to Horowitz, et al. (Horowitz 649), Shanbrom '945; 5,648,472, titled PROCESS FOR PREPARING VIRUS-INACTIVATED IMMUNOGLOBULIN SOLUTIONS, issued Jul. 15, 1997, to Gehringer, et al. (Gehringer '472); 6,372,216 titled METHOD OF PRODUCING SPECIFIC IMMUNOGLOBULIN TO BLOCK HCV INFECTION, issued Apr. 16, 2002 to Piazza (Piazza '216); 6,468,733 titled METHOD OF THE INACTIVATION OF VIRUSES BY A SOLVENT-DETERGENT COMBINATION AND NANOFILTRATION issued Oct. 22, 2002 to Nur. et al. (Nur '733); and 6,517,987 titled FRANGIBLE COMPOUNDS FOR PATHOGEN INACTIVATION issued Feb. 4, 2003 to Cook et al. (Cook '987). Each manufacturer of such plasma products may use slightly different detergents and conditions in the SD treatment. It should be noted that different removal techniques may be used by the different manufacturers depending upon the specific process utilized and/or products involved.
In order to assure the safety of blood products against non-enveloped viruses, a second viral inactivation (e.g. pasteurizaiton, dry-heat) or a removal step is currently, usually employed (e.g. fractionation). There is, to date, no inactivation method effective against prions, including any of the currently used methods which preserve the activity of therapeutically active proteins. Fractionation is the only known effective removal step as reported in Vox Sanguinis, Blackwell Publishing, Ltd, 84, 174-187, 2003.
It has been shown that formaldehyde and/or phenol inactivates both enveloped and non-enveloped viruses. Use of formaldehyde/phenol in an SD treated product would assure enveloped and non-enveloped virus inactivation. However, currently such treatments must be done independently resulting in longer process time and handling losses. As Prince '189 teaches, “For instance, it is known to attempt to inactivate hepatitis B virus by contact with an aldehyde such as formaldehyde whereby crosslinking to the protein is effected and the hepatitis B virus is inactivated.”
Louderback '165 teaches inactivating HTLV-III virus in blood or blood components by treatment with phenol, formaldehyde or mixtures thereof. However, use of formaldehyde has, in the past, not been considered suitable for inactivation of viruses in plasma, as is taught in Prince '189, “It is to be understood that the problems of inactivation of hepatitis in plasma are distinct from the problems of inactivation of the viruses themselves due to the copresence of the desirable components of the plasma. Thus, while it is known how to inactivate the hepatitis B virus, crosslinking agents, e.g. glutaraldehyde, nucleic acid reacting chemical e.g.: BPL [beta propiolactone], or formaldehyde, or oxidizing agents e.g. Clorox etc. it has been believed that these methods are not suitable for the inactivation of the virus in plasma due to the observation that most of these inactivating agents (sodium hypochlorite, formaldehyde, .beta.- propiolactone) denature the valuable proteinaceous components of the plasma.”
For each SD treatment and associated SD chemical separation, it is normal practice to set up a standard protocol which is particularly specified for each SD treatment. To minimize training and related documentation, it is preferred that any augmentation of such treatments and separations require little or no effect on the specified standard protocol.
For an augmented SD treatment which inactivates both enveloped and non-enveloped viruses to be effective, the SD and augmenting portion of the treatment should, therefore, be able to be performed simultaneously, effecting rapid enveloped and non-enveloped viral kill and, potentially, prion inactivation. Removal of all reagents, so employed, at the end of a blood plasma process intermediates treatment should be accomplished by standard methods, e.g. precipitation or chromatography to recover the therapeutic proteins. It would be advantageous, as well, for incubation to be at the temperature and for the times necessary for the effectiveness of SD treatment, for example 27° C. (±3° C.) for 6 hours. Typical concentrations in the final plasma mixture of the SD chemicals would be Triton X-100—0.5% to 1.0% (5000-10,000 ppm), and/or Tween-80—0.5%-1.0% (5000-10,000 ppm) and Tri-n-Butyl Phosphate—0.3% (3000 ppm).
Louderback in U.S. Pat. No. 4,833,165, titled METHOD OF INACTIVATING HTLV-III VIRUS IN BLOOD issued May 23, 1989 to Louderback (Louderback '165) describes a sterilization treatment of washed red blood cells using a solution containing formaldehyde and/or phenol which was shown to be effective to inactivate HTLV-III (now called HIV-1) so that one could transfuse virally inactivated sterile treated red blood cells to a patient. Work with a variety of viruses and bacteria and parasitic protozoa showed likewise inactivation in so treated red blood cells permitting subsequent transfusion into a patient without risk of disease transmission.
A summary of viral inactivation data for the formaldehyde/phenol in red blood cells derived from Louderback '165, CDC (March 1992), and AABB (Nov. 1992)] is provided in Table I. Formaldehyde solution is very water soluble and hydrophilic. Phenol in solution is very lipid soluble and lipophilic. A combination of these two different sterilizing liquids acting upon both enveloped (having a lipid outer shelf) and non-enveloped viruses at the same time causes a synergistic action of inactivation gr ater than either alone. Treatm nt time used was 20-30 minutes at room temperature (20° C.±2° C.) with 3000 ppm formaldehyde and/or phenol.
TABLE ILog killedgenomemedium*Enveloped VirusHIV-1>=4.33RNArbcFIVall killedRNArbcSindbis>=6.71RNArbcVSV>=7.00RNArbcCMV>=5.23DNArbcVaccina>=4.79DNArbcNon-enveloped VirusPolio virusType 1>=4.20RNAplasma or rbcParvo virus B19 (human)>=5.00DNAplasmaParvo virus (pig)>=4.0 DNAplasma*rbc = red blood cells 
Formaldehyde and/or phenol also inactivates bacteria and protozoans in blood cell mixtures. Table II, found hereunder, provides a summary of data for bacteria and parasitic protozoans.
TABLE IIInactivation of Bacteria & Protozoans in Whole BloodLogs inactivatedBacteriaYersinia entercolitica2*Treponema pallidum8*Borrelia burgdorferi8*ProtozoansTrypanosoma cruzi8-9*Leishmania tropica6*Plasmodium berghei8-9*Babesia microti8**all added organisms were inactivated 
As used herein, the term “process intermediate” is defined to be a solution containing one or more therapeutic proteins, carbohydrates or glycoproteins that has been processed to produce a therapeutic product intended for administration to humans, animals or plants. A “process intermediate” may be derived from human or animal blood, plasma or plasma fractions; recombinant cells or culture media, tissue culture cells or media, cell culture cells or media, insect or other invertebrate cells or media or from any biological tissues or fluids.